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Ryr2 calcium leakage

Phonindra Nath Das, Ajay Kumar, Nandadulal Bairagi, Samrat Chatterjee
Calcium homeostasis is a key factor in the regulation of cardiac excitation-contraction coupling. Calcium dynamics in cardiomyocytes is governed by ATP which depends on insulin dependent glucose concentration, via the glucose transporter type 4 (GLUT4) transporter. It would therefore be interesting to see how calcium dynamics changes in a cardiomyocyte under diabetic conditions. We proposed and analysed a four dimensional ordinary differential equation (ODE) model to capture the interdependency of calcium dynamics on glucose uptake and ATP generation...
September 26, 2017: Molecular BioSystems
Renaud Bussiere, Alain Lacampagne, Steven Reiken, Xiaoping Liu, Valerie Scheuerman, Ran Zalk, Cécile Martin, Frederic Checler, Andrew R Marks, Mounia Chami
Alteration of ryanodine receptor (RyR)-mediated calcium (Ca2+ ) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca2+ release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the β-amyloid precursor protein (βAPP) harboring the familial double Swedish mutations (APPswe)...
June 16, 2017: Journal of Biological Chemistry
Julia Ritterhoff, Mirko Völkers, Andreas Seitz, Kristin Spaich, Erhe Gao, Karsten Peppel, Sven T Pleger, Wolfram H Zimmermann, Oliver Friedrich, Rainer H A Fink, Walter J Koch, Hugo A Katus, Patrick Most
Restoring expression levels of the EF-hand calcium (Ca(2+)) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca(2+) handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca(2+) resequestration appears critical for S100A1's cyclic adenosine monophosphate-independent inotropic effects but raises concerns about potential diastolic SR Ca(2+) leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and ryanodine receptors (RyR2s) in experimental HF...
August 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
Xiangsheng Yang, Tiannan Wang, Xi Lin, Xiaojing Yue, Qiongling Wang, Guoliang Wang, Qin Fu, Xun Ai, David Y Chiang, Christina Y Miyake, Xander H T Wehrens, Jiang Chang
RATIONALE: Rnd3, a small Rho GTPase, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation. The biological function of Rnd3 in the heart remains unexplored. OBJECTIVE: To define the functional role of the Rnd3 gene in the animal heart and investigate the associated molecular mechanism. METHODS AND RESULTS: By loss-of-function approaches, we discovered that Rnd3 is involved in calcium regulation in cardiomyocytes...
January 2, 2015: Circulation Research
Wei Wang, Andrew P Landstrom, Qiongling Wang, Michelle L Munro, David Beavers, Michael J Ackerman, Christian Soeller, Xander H T Wehrens
Expression silencing of junctophilin-2 (JPH2) in mouse heart leads to ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca(2+) leak and rapid development of heart failure. The mechanism and physiological significance of JPH2 in regulating RyR2-mediated SR Ca(2+) leak remains elusive. We sought to elucidate the role of JPH2 in regulating RyR2-mediated SR Ca(2+) release in the setting of cardiac failure. Cardiac myocytes isolated from tamoxifen-inducible conditional knockdown mice of JPH2 (MCM-shJPH2) were subjected to confocal Ca(2+) imaging...
November 1, 2014: American Journal of Physiology. Heart and Circulatory Physiology
Can M Sag, Hendrik A Wolff, Kay Neumann, Marie-Kristin Opiela, Juqian Zhang, Felicia Steuer, Thomas Sowa, Shamindra Gupta, Markus Schirmer, Mark Hünlich, Margret Rave-Fränk, Clemens F Hess, Mark E Anderson, Ajay M Shah, Hans Christiansen, Lars S Maier
Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week)...
November 2013: Basic Research in Cardiology
Kirsi Kujala, Jere Paavola, Anna Lahti, Kim Larsson, Mari Pekkanen-Mattila, Matti Viitasalo, Annukka M Lahtinen, Lauri Toivonen, Kimmo Kontula, Heikki Swan, Mika Laine, Olli Silvennoinen, Katriina Aalto-Setälä
BACKGROUND: Induced pluripotent stem cells (iPSC) provide means to study the pathophysiology of genetic disorders. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited ion channel disorder predominantly caused by mutations in the cardiac ryanodine receptor (RyR2). In this study the cellular characteristics of CPVT are investigated and whether the electrophysiological features of this mutation can be mimicked using iPSC -derived cardiomyocytes (CM). METHODOLOGY/PRINCIPAL FINDINGS: Spontaneously beating CMs were differentiated from iPSCs derived from a CPVT patient carrying a P2328S mutation in RyR2 and from two healthy controls...
2012: PloS One
Hiroshi Watanabe, Björn C Knollmann
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by VT induced by adrenergic stress in the absence of structural heart disease and high incidence of sudden cardiac death. The diagnosis is made based on reproducible ventricular tachyarrhythmias including bidirectional VT and polymorphic VT during exercise testings. Two causative genes of CPVT have been identified: RYR2, encoding the cardiac ryanodine receptor (RyR2) Ca(2+) release channel, and CASQ2, encoding cardiac calsequestrin...
November 2011: Journal of Electrocardiology
Yi-Hsin Chan, Lung-Sheng Wu, Yung-Hsin Yeh, Chia-Tung Wu, Chun-Li Wang, Nazar Luqman, Wei-Jan Chen, Tzu-Shiu Hsu, Chi-Tai Kuo
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a serious disease with a high mortality but its management is limited. The aim of this study was to investigate specific target sites for therapy in order to find potential management strategies for CPVT. METHODS AND RESULTS: The mutant Ryanodine receptor 2 (RyR2) with reduced stored-overloaded-induced Ca²⁺ release (SOICR) threshold was incorporated into the Luo-Rudy dynamic (LRd) cell model to elucidate the underlying pathologies of CPVT...
2011: Circulation Journal: Official Journal of the Japanese Circulation Society
Dayue Darrel Duan
No abstract text is available yet for this article.
April 2010: Hypertension
Zhuying Guo, Shiting Wang, Qiang Jiao, Manghua Xu, Fenghou Gao
The effects of a small interfering RNA targeting ryanodine receptor 2 (si-Ryr2) on cardiomyocytes injury following a simulated ischemia-reperfusion (I/R) were investigated. Pretreated with si-Ryr2 or ryanodine, primary cultures of neonatal rat cardiomyocytes were subjected to a protocol of simulated I/R. Compared with control, the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS) was significantly augmented after I/R. Concomitant with these, cell injury assessed by Annexin V/PI staing, mitochondria membrane potential (DeltaPsim) and the leakage of lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) were aggravated...
March 2010: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mihail G Chelu, Satyam Sarma, Subeena Sood, Sufen Wang, Ralph J van Oort, Darlene G Skapura, Na Li, Marco Santonastasi, Frank Ulrich Müller, Wilhelm Schmitz, Ulrich Schotten, Mark E Anderson, Miguel Valderrábano, Dobromir Dobrev, Xander H T Wehrens
A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice...
July 2009: Journal of Clinical Investigation
Takayuki Tsuneda, Takeshi Yamashita, Takeshi Kato, Akiko Sekiguchi, Kouichi Sagara, Hitoshi Sawada, Tadanori Aizawa, Long-Tai Fu, Akira Fujiki, Hiroshi Inoue
BACKGROUND: Since the prevalence of atrial fibrillation (AF) increases progressively with aging, especially in men, we hypothesized that testosterone might affect the occurrence of AF. METHODS AND RESULTS: We examined the electrophysiological properties of the atria in isolated-perfused hearts of sham-operated male (SM), female (SF), orchiectomized male with and without administration of testosterone (ORCH-T and ORCH), and ovariectomized female (OVX) Sprague-Dawley rats...
September 2009: Journal of Cardiovascular Electrophysiology
Zhu-ying Guo, Qiang Jiao, Shi-ting Wang, Mang-hua Xu, Feng-hou Gao
OBJECTIVES: To block the synthesis of ryanodine receptor 2 (RyR2) in myocardial cells by RNA interference and to investigate its biological impact on ischemia-reperfusion (I/R) in rat myocardial cells. METHODS: Rat myocardial cells were isolated and cultured for an I/R model in vitro. RNA interference technique was used to block the synthesis of RyR2 in myocardial cells. Changes of LDH level, apoptosis, RyR2 mRNA expression and cytosolic Ca(2+) concentration were analyzed accordingly...
November 2008: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Jian Zhong, Jing Chen, Tingbin Cao, Lijuan Wang, Weiguo Zhang, Daoyan Liu, Zhiming Zhu
1. Cardiac ryanodine RyR2 receptors regulate Ca(2+) release from the sarcoplasmic reticulum (SR). FK506 binding protein (FKBP) 12.6 prevents aberrant SR Ca(2+) leakage during diastole, thereby maintaining the integrity of RyR2 function. Previous studies have focused mainly on FKBP12.6 deficiency and so the pathophysiological consequences of FKBP12.6 overexpression remain unclear. Herein, we investigate the effect of FKBP12.6 overexpression on cardiac hypertrophic and apoptotic signalling. 2. Human FKBP12.6 cDNA was cloned into pAdTrack-CMV and the resulting plasmid, along with a control empty plasmid, were transfected into bacteria...
February 2009: Clinical and Experimental Pharmacology & Physiology
Min Fu, Ru-Xin Li, Li Fan, Guo-Wei He, Kent L Thornburg, Zhao Wang
The present study established a model of RyR(2) knockdown cardiomyocytes and elucidated the role of RyR(2) in aconitine-induced arrhythmia. Cardiomyocytes were obtained from hearts of neonatal Sprague-Dawley rats. siRNAs were used to down-regulate RyR(2) expression. Reduction of RyR(2) expression was documented by RT-PCR, western blot, and immunofluorescence. Ca(2+) signals were investigated by measuring the relative intracellular Ca(2+) concentration, spontaneous Ca(2+) oscillations, caffeine-induced Ca(2+) release, and L-type Ca(2+) currents...
June 1, 2008: Biochemical Pharmacology
Barnabas Gellen, María Fernández-Velasco, François Briec, Laurent Vinet, Khai LeQuang, Patricia Rouet-Benzineb, Jean-Pierre Bénitah, Mylène Pezet, Gael Palais, Noémie Pellegrin, Andy Zhang, Romain Perrier, Brigitte Escoubet, Xavier Marniquet, Sylvain Richard, Fréderic Jaisser, Ana María Gómez, Flavien Charpentier, Jean-Jacques Mercadier
BACKGROUND: Ca(2+) release from the sarcoplasmic reticulum via the ryanodine receptor (RyR2) activates cardiac myocyte contraction. An important regulator of RyR2 function is FKBP12.6, which stabilizes RyR2 in the closed state during diastole. Beta-adrenergic stimulation has been suggested to dissociate FKBP12.6 from RyR2, leading to diastolic sarcoplasmic reticulum Ca(2+) leakage and ventricular tachycardia (VT). We tested the hypothesis that FKBP12.6 overexpression in cardiac myocytes can reduce susceptibility to VT in stress conditions...
April 8, 2008: Circulation
Daniel R Gonzalez, Farideh Beigi, Adriana V Treuer, Joshua M Hare
Altered Ca(2+) homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via S-nitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca(2+) homeostasis. Diastolic Ca(2+) levels are elevated in NOS1(-/-) and NOS1/NOS3(-/-) but not NOS3(-/-) myocytes compared with wild-type (WT), suggesting diastolic Ca(2+) leakage...
December 18, 2007: Proceedings of the National Academy of Sciences of the United States of America
Georgina M Ellison, Daniele Torella, Ioannis Karakikes, Saranya Purushothaman, Antonio Curcio, Cosimo Gasparri, Ciro Indolfi, N Tim Cable, David F Goldspink, Bernardo Nadal-Ginard
A hyperadrenergic state is a seminal aspect of chronic heart failure. Also, "Takotsubo stress cardiomyopathy," is associated with increased plasma catecholamine levels. The mechanisms of myocyte damage secondary to excess catecholamine exposure as well as the consequence of this neurohumoral burst on cardiac stem cells (CSCs) are unknown. Cardiomyocytes and CSCs were exposed to high doses of isoproterenol (ISO), in vivo and in vitro. Male Wistar rats received a single injection of ISO (5 mg kg-1) and were sacrificed 1, 3, and 6 days later...
April 13, 2007: Journal of Biological Chemistry
Zhaokang Yang, Noriaki Ikemoto, Graham D Lamb, Derek S Steele
OBJECTIVE: In vitro experiments have shown that the ryanodine receptor-2 (RyR2) central domain peptide DPc10 (Gly(2460)-Pro(2495)) mimics channel dysfunction associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) by acting competitively to reduce stabilizing interactions between the N-terminal and central domains. In the present study, DPc10 was used as a tool to establish an adult cell model of the disease and to analyse the underlying mechanisms. METHODS: Rat ventricular myocytes were permeabilized with saponin and perfused with solutions approximating the intracellular milieu containing fluo-3...
June 1, 2006: Cardiovascular Research
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